A wide variety of disease conditions are characterized by the presence of elevated concentrations of cytokines and/or pathogens in the blood stream. Some such conditions are treated by therapies designed to kill the pathogen, e.g. through the administration of drugs, e.g., anti-infective pharmaceuticals. Some other conditions are treated by therapies that attempt to reduce the concentration of blood-borne cytokines or pathogens in the patient. Other diseases are treated by therapies that attempt to directly remove only specific components from the patient's blood.
For example, Guillian-Barre syndrome is currently understood to be an autoimmune disorder triggered by viral infection that stimulates the body's immune system to over produce antibodies or other proteins which can attack the patient's nervous system, causing increasing levels of paralysis. Most patients recover over time, though such patients appear to be susceptible to recurrance of the condition from subsequent viral infections. One method for treating Guillian-Barre syndrome involves plasmapheresis to ‘clean’ the patient's blood by removing antibodies believed to be attacking the patient's nervous system.
Certain biologically active carbohydrates and polysaccharides can remove harmful substances from blood and biological fluids.
Heparin is a polysaccharide that can be isolated from mammalian tissue. It has a very specific distribution in mammalian tissue; being present only in the basophilic granules of mast cells. Since its discovery in 1916 by the American scientist McLean, heparin has been recognized for its ability to prevent blood from clotting, and for its relatively short half-life in the body. Systemic heparin, administered by injection of the free drug, has been used clinically for more than 50 years as a safe and effective blood anticoagulant and antithrombotic agent. The effects of heparin on blood coagulation/clotting diminish fairly quickly after administration is halted, making its use during surgery and other procedures effective and safe. That is, heparin's anticoagulant and antithrombogenic properties are useful during many medical procedures, for example to minimize undesirable interactions between blood and the man-made surfaces of extracorporeal circuits. Once the procedure is over, the administration of heparin may then be terminated. The heparin concentration in the patient's blood diminishes to a safe level within a few hours because of its short half life in the body. This is particularly important following surgery when healing depends on the ability of blood to clot at the surgical site to avoid bleeding complications. In addition to its well established and continuing use in the treatment of thromboembolic disorders, and the prevention of surface-induced thrombogenesis, heparin has more recently been found to have a wide range of other functions apparently unrelated to its function as an anticoagulant. For example, a large number of proteins in blood are now known to bind with high affinity, to heparin and/or the closely-related polysaccharide heparan sulfate which is also found in animal tissue, including the blood-contacting luminal surface of healthy blood vessels (where it may contribute to preventing circulating blood from clotting on contact with the walls of the blood vessels). Some examples are antithrombin (AT), fibronectin, vitronectin, growth factors (e.g. the fibroblast growth factors, the insulin like growth factors, etc.). Human serum albumin (HSA) also binds to heparin, but with a lower affinity despite its high concentration in blood.
Others have considered utilizing the selective adsorption properties of systemic, free heparin for hindering infections, by introducing heparin fragments and/or so-called sialic-containing fragments directly into the vascular system. This therapy was based on the assumption that these fragments would bind to the lectins on the microbes and block them so they could not bind to the receptors on the mammalian cell surface. Although this approach has been investigated by many scientists, only limited success has been reported to date. The most common problem has been bleeding complications associated with the large amounts of free heparin introduced into the blood stream, e.g., by injection, to achieve a clinically-useful reduction of pathogenic microbes. The present invention does not require the use of any free, systemic heparin for efficacy, and thus may eliminate bleeding complications. This is accomplished by permanently binding the heparin or heparan sulphate to a solid substrate with high surface area, and exposing it to the blood within a cartridge or filter containing this adsorption media.
The following references deal with issues discussed above:
Weber et al. (Weber V, Linsberger I, Ettenauer M, Loth F, et al. Development of specific adsorbents for human tumor necrosis factor-alpha: influence of antibody immobilization on performance and biocompatibility. Biomacromolecules 2005; 6: 1864-1870) reported significant in vitro binding of TNF using cellulose micro particles coated with a monoclonal anti-TNF antibody, while Haase et al. (Haase M, Bellomo R, Baldwin I, Haase-Fielitz A, et al. The effect of three different miniaturized blood purification devices on plasma cytokine concentration in an ex vivo model of endotoxinemia. Int J Artif Organs 2008; 31: 722-729) reported a significant reduction in IL-1ra, but not in IL-6, using a similar ex vivo methodology as ours but with a porous adsorption device. In vivo, Mariano et al. (Mariano F, Fonsato V, Lanfranco G, Pohlmeier R, et al. Tailoring high-cut-off membranes and feasible application in sepsis-associated acute renal failure: in vitro studies. Nephrol Dial Transplant 2005; 20: 1116-1126) are able to significantly reduce several circulating cytokines with hemoperfusion and a high cut-off polysulphone membrane, but also reported a loss of serum albumin. The putative clinical relevance of these findings are demonstrated by Schefold et al. (Schefold J C, von Haehling S, Corsepius M, Pohle C, et al. A novel selective extracorporeal intervention in sepsis: immunoadsorption of endotoxin, interleukin 6, and complement-activating product 5a. Shock 2007; 28: 418-425) who in a randomized study of 33 patients with septic shock are able to simultaneously reduce circulating endotoxin, IL-6, and C5a levels by selective immunoadsorption, resulting in improved organ function.